G. Nicholas Verne, M.D. Revision to Grant # AT005291 PROJECT SUMMARY Irritable bowel syndrome (IBS) is a common gastrointestinal disorder that is estimated to affect 20% of the US population. IBS patients have significantly decreased quality of life and utilize large amounts of health care resources. IBS patients suffer from chronic abdominal pain associated with diarrhea, constipation, and/or bloating (Verne & Cerda, 1997). Several mechanisms that may lead to IBS have been proposed including: alterations in receptors and neuropeptides, bacterial overgrowth and altered microbiota, altered intestinal transit, anxiety and depressive symptoms, and increased intestinal membrane permeability. Several recent studies have shown that diarrhea-predominant IBS (D-IBS) patients have increased intestinal permeability that may lead to chronic gastrointestinal symptoms (Dunlop et al., 2006; Spiller 2000; 2007; Zhou et al., 2009b). Our laboratory recently evaluated diarrhea-predominant IBS patients and reported that they have increased membrane permeability (Zhou et al, 2009). We now have obtained preliminary evidence that oral glutamine supplementation restores membrane permeability and improves chronic gastrointestinal symptoms in these IBS patients. Based on these new findings, we hypothesize that oral glutamine supplementation will improve the IBS Symptom Severity Scale and restore intestinal membrane permeability in diarrhea-predominant IBS patients. We propose to conduct a randomized, double-blind, placebo-controlled clinical trial studying glutamine 10 g po tid compared to placebo 10 g po tid for 8 weeks in 100 diarrhea-predominant IBS patients. The IBS Symptom Severity Scale and intestinal membrane permeability will be measured at baseline, 2, 4, 6, and at 8 weeks.